Follicular dendritic cell sarcoma (FDCS), first reported
in 1986 by Monda et al. is a rare tumor that arises from
the follicular dendritic cells1. Principally recognized
as a lymph nodal disease, extremely rare occurrences of
extranodal FDCS’s are reported in the liver, lung, spleen,
soft tissues, mediastinum, gastrointestinal tract, etc.
Involvement of the head and neck region is extremely
uncommon with only few case reports and small series. The
tonsil is the most commonly reported site of involvement
in the head and neck region2-4. Spindle to epithelioid
cells, intimately admixed with lymphocytes, is the typical
histology. However the morphologic spectrum of FDCS is
broad, inviting diverse clinicopathologic entities into the
list of differential diagnosis.

Extreme rarity at extranodal sites coupled with lack
of awareness of its varied morphologic features makes
diagnosis of FDCS challenging and fraught with pitfalls.
Herein, we report a case of FDCS arising in the larynx, a
heretofore unreported site till date.

A 59-year-old male patient presented with a history
of swelling on the left side of the neck for eight months,
hoarseness of voice for three months, dysphagia for one
month, and mild breathlessness. The patient had undergone
treatment for pulmonary tuberculosis 25 years back. He
gave a history of smoking one packet per day of beedi (a thin Indian cigarette, filled with tobacco flakes and rolled in
leaf) since 18 years of age.

On examination, bilateral rhonchi were noted. Left level
III cervical lymph node was enlarged and cystic. On
direct laryngoscopy, there was a large proliferative growth
involving epiglottis, bilateral aryepiglottic folds, bilateral
pharyngoepiglottic folds, bilateral vallecula, bilateral false
vocal cords and left pyriform sinus. The glottic chink was
compromised. The right pyriform sinus, and post cricoid
area were free. The right vocal cord was mobile.

On chest X-Ray, ill-defined patchy opacities were seen in
right upper and left mid zone. Few fibrocalcific opacities
were also seen, suggestive of post-tubercular fibrosis with
cavitation. On computerized tomography (CT) scan, a
mass was seen involving the posterior 1/3rd of the tongue,
vallecula, epiglottis, and both sides of the hypopharynx
and supraglottis. The pre-epiglottic space was effaced.
The mass was crossing the midline and involving the
lateral hypopharyngeal wall, and invading the prevertebral
muscles at the C4-C5 level. No cartilage erosion was seen.
A large necrotic lymph node was noted at left level III.
The patient underwent a laryngoscopic biopsy from the
supraglottis. Subsequently, the patient developed aspiration
and breathlessness for which he underwent an emergency
tracheostomy.

In view of the morphological and immunohistochemical
features, a diagnosis of high grade follicular dendritic cell
sarcoma involving the larynx was proffered.

Due to involvement of the vallecula, the mass was
considered unresectable, hence chemotherapy followed by
reassessment was planned. However, the patient refused
further treatment and was subsequently lost to follow-up.

Follicular dendritic cells function primarily as antigen
presenting cells to B cells, hence are involved in humoral
immunity2,5. Tumors arising from follicular dendritic
cells are called follicular dendritic cell sarcoma, and are
classified under the histiocytic and dendritic cell neoplasms in the World Health Organization classification of tumors6.

Etiopathogenetic factors of FDCS’s are yet to be clearly
defined. In view of some cases arising in the background
of Castleman disease, a hyperplasia-dysplasia-neoplasia
sequence, akin to colorectal cancer, has been proposed for
FDCS’s2,4. Other possible etiological factors proposed
are EBV infection, possible association with autoimmune
disorders, and origin from a common multipotent
mesenchymal stem cell2,4,6.

In a pooled analysis of cases reported from 1978-2012,
Saygin et al. found 343 cases of FDCS’s in the literature,
with a mean age at diagnosis being 50 years, and an almost
equal male-female predilection4. Though initially
considered a nodal disease, they observed that FDCS was
increasingly being reported at extranodal sites, including
liver, spleen, soft tissues, mediastinum, gastro-intestinal
tract, mesentery, bone, pancreas, and skin. Other rare sites,
reported as isolated cases, include the kidney, pleura, testis,
ovary, bladder, adrenal, dura, and thymus4. Recently,
Pang et al. reviewed English literature specifically for head
and neck region FDCS and found 97 cases, most commonly
involving the lymph nodes (40%), oropharynx (24%) and
soft tissues of the head and neck (10%)7. In a larger
review, Li et al. analyzed 137 cases of head and neck FDCS,
with an equal male to female distribution, similar to FDCS
elsewhere in the body8. The mean age at diagnosis was
46 years (9-79 years). Of the 137 cases, 65 were cervical
nodal FDCS and 72 were extranodal. The most common
extranodal site was the tonsil, followed by the nasopharynx,
parapharyngeal space, palate, thyroid and parotid8.
However, involvement of the larynx by FDCS, as seen in
the present case, has not been reported till date, to the best
of our knowledge.

Clinically, the majority of the cases present as slowly growing
painless masses, which on gross appearance are usually well
circumscribed and solid4. Microscopically, FDCS’s are
composed of neoplastic follicular dendritic cells intimately
admixed with lymphocytes. Two types of histological
patterns are recognized9. In the low grade pattern, the
tumor cells are uniform, spindle to ovoid, arranged in short
fascicles, whorls, or nodules. Nuclei show mild atypia, pale
chromatin, distinct nuclear membrane and visible nucleoli.
Hyperchromasia is not typical. The mitotic count is usually
low. Admixture with lymphocytes sprinkled throughout
the tumor, with or without plasma cells, is seen in more
than 90% of the cases4,9. Depending on the location,
these tumors are often histologically confused with diverse
pathologic entities like nerve sheath tumors, gastrointestinal stromal tumors (GIST), inflammatory myofibroblastic
tumor (IMT), fibrous histiocytomas, meningiomas, Type A
thymoma, and granulomatous inflammation.

In contrast, in the high grade pattern, the tumor cells are
arranged predominantly in diffuse sheets, with areas of
necrosis. The tumor cells have epithelioid or pleomorphic
morphology, with marked nuclear atypia and frequent
mitosis. Lymphocytic infiltrate, considered characteristic
of FDCS, may be sparse4,9. High grade FDCS may
be mistaken for poorly differentiated/ undifferentiated
carcinoma, melanoma, lymphoma, malignant sarcoma, and
other histiocytic and dendritic cell neoplasms. In the current
case, the tumor resembled a poorly differentiated squamous
cell carcinoma (SCC), with epithelioid appearance, areas
of necrosis, and frequent mitosis, albeit with a striking
admixture of lymphocytes, which served as an important
clue, leading us to include FDCS markers in our differential
diagnoses. Immunohistochemistry (IHC) is essential for
confirming the diagnosis. On IHC, FDCSs are positive for
CD21, CD35, CD23, vimentin, desmoplakin, clusterin and
fascin. They are variably positive for CD68, EMA and S100
protein9. MIB-1 labeling indices range from 1-25% (mean
13%)6,9. Recently podoplanin (D2-40), has been shown
to be a sensitive marker for FDCS, and was also positive in
our case10. However, not infrequently, staining for many
of the FDCS markers is focal. In their review, Li et al. found
positivity rates for CD21, CD35, CD23, and vimentin to
be 85%, 55%, 31.7% and 38.3%, respectively8. Hence it
is imperative to use more than one FDCS marker and to
repeat the markers on additional blocks when the index of
suspicion is high4. In the present case too, the tumor was
strongly immunopositive for both CD23 and podoplanin,
however, it was immunonegative for CD21 (possibly
because the specimen was a biopsy with limited amount of
tumor tissue), highlighting the importance of performing
multiple markers for FDCS. Immunohistochemistry
for CD35 is not available at our center. These tumors are
negative for immunohistochemical markers of the majority
of the entities in the differential diagnosis, including
cytokeratin, HMB45, CD3, CD20, ALK-1, CD30, CD34,
CD79a, lysozyme, CD1a, leucocyte common antigen
(LCA), and myeloperoxidase9.

Extranodal FDCS is still an under-recognized entity,
especially in the head and neck. It poses a potential
diagnostic pitfall for pathologists, because even though the
histological and immunohistochemical features are quite
characteristic, it is commonly confused with more common
and more aggressive tumors such as squamous carcinoma,
sarcomatoid carcinoma, melanoma, lymphoma and mesenchymal tumors. Hence, the diagnosis is often missed,
especially in a needle biopsy, primarily due to a failure to
consider FDCS in the differential diagnosis, and thus not
employing an appropriate immunohistochemical panel.
Also, the large panel of IHC markers necessitated to rule
out other diagnoses may not be available at smaller centers.
Because of the wide variety of differentials, and the rarity of
FDCS, a stepwise approach eliminating the more common
conditions, before proceeding to specific FDCS markers, is
generally more cost effective.

FDCSs are considered to be intermediate grade sarcoma
because of the substantial risk of local recurrence (23-43%)
and metastasis (21-27%) with a mortality rate of about 3-7%.
In extranodal FDCS, the 2- and 5-year survival rates are
only 62.3 and 27.4% respectively4,7. Some authors have
suggested that features purporting an adverse outcome,
similar to other soft tissue sarcomas, include young age
at diagnosis, intra-abdominal location, large tumor size
(>6 cm), coagulative necrosis, absence of lymphocytes,
significant nuclear pleomorphism and high mitotic count
(>5/10HPF)2,4,6,9.

Current treatment approach for FDCS at all sites, including
the head and neck, is surgical excision with clear margins,
with or without adjuvant chemotherapy or radiotherapy6-8. In advanced or metastatic disease, a combined
approach, with diverse modalities, including chemotherapy
and radiotherapy, have been attempted4. In the present
case, as the disease was unresectable at presentation and
chemotherapeutic intervention was planned; however the
patient refused treatment, and was lost to follow up.

In summary, we report the first case of extranodal FDCS
arising in the larynx, to the best of our knowledge. Its rarity,
wide morphological spectrum and long list of differential
diagnostic entities make FDCS an under-recognized
disease and susceptible to diagnostic pitfalls. A high index
of suspicion together with a judicious use of IHC can
help segregate FDCS from other spindle cell or poorly
differentiated epithelioid tumors.